Coronary Endothelial Dysfunction Prevented by SK Channel Activator in Mice and Patients with Diabetes

Abstract Objectives We investigated coronary endothelial protection of a small-conductance calcium-activated potassium (SK) channel activator against a period of cardioplegic-hypoxia and re-oxygenation (CP-H/R) injury in mice and patients with or without diabetes (DM). Methods Mouse small coronary arteries/heart endothelial cells (MHECs) or human coronary arterioles were dissected from the harvested hearts of mice (n = 16/group) or from discarded right atrial tissue samples of patients with or without DM (n = 8/group). SK-current density of MHECs was measured. The in-vitro small-arteries/arterioles, MHECs, and human coronary arterial endothelial cells (HCAECs) were subjected to 60-minutes of CP-hypoxia and then oxygenated for 60-minutes. Vessels were treated with or without the selective SK-activator NS309 5-minutes before and during CP-hypoxia. Results Diabetes and/or CP-H/R significantly inhibited the total SK-currents of MHECs and HCAECs. DM and/or CP-H/R significantly diminished mouse coronary relaxation response to NS309. Administration of NS309 immediately pre- and during CP-hypoxia significantly improved the recovery of coronary endothelial function, demonstrated by increased relaxation responses to ADP and substance P when compared with the controls (p Conclusions Application of NS309 immediately before and during CP-hypoxia protects mouse and human coronary microvasculature against CP-H/R injury, but this effect was diminished in the diabetic coronary microvasculature. SK inhibition/inactivation and/or SK internalization/redistribution may contribute to CP-H/R-induced coronary-endothelial and vascular-relaxation dysfunction.